http://theses.ncl.ac.uk/jspui/handle/10443/96 Sat, 02 May 2026 07:11:51 GMT 2026-05-02T07:11:51Z http://theses.ncl.ac.uk/jspui/handle/10443/6752 Title: Cyclin B1 regulation and APC/C processivity in mouse oocyte meiosis I Authors: Kerridge, Scott Thomas Abstract: Chromosome alignment is orchestrated by the activity of CDK1 bound to its coactivator cyclin B1. Equally important, chromosome segregation is orchestrated by termination of CDK1 activity, driven by cyclin B1 destruction. Both events must be precisely timed by APC/C (Anaphase Promoting Complex/Cyclosome) activity, an E3 ligase that targets cell cycle proteins for destruction via the ubiquitin-proteasome pathway. In mitosis, this system is rapid, robust, and well-studied. Critically, through oocyte chromosome alignment, CDK1 and APC/C activities must be regulated differently, over substantially longer time frames. Specifically, the APC/C must first be dampened to prevent cyclin B1 destruction and CDK1 activity loss as chromosomes begin aligning. This is followed by a period of non-CDK1-bound cyclin B1 destruction during final alignment stages, followed by CDK1-bound-cyclin B1 destruction once fully aligned. This ordering is vital to minimise errors that otherwise cause the cell to arrest (infertility) or produce an embryo that is incompatible with life (miscarriage). However, little is published regarding the molecular mechanism of cyclin B1 targeting in oocytes, or indeed the wider landscape of any APC/C substrate ordering. To address this, I have expressed fluorescent versions of cyclin B1 and APC/C substrates in live mouse oocytes, utilising time-lapse fluorescence microscopy to map their levels and movements through meiosis I. Additionally, I mutated short linear motifs within these substrates, as well as APC/C subunit knockdowns to obtain mechanistic insight into substrate targeting. I reveal that cyclin B1 harbours a motif which boosts its affinity for a specific form of the APC/C during chromosome alignment. This form of the APC/C does not exist globally across the cell, but likely in high priority areas across this spindle zone. This and other insights, describe novel aspects of cell cycle regulation that are critical to produce healthy eggs Description: Ph. D. Thesis. Wed, 01 Jan 2025 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6752 2025-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/6750 Title: Causal neural mechanisms for decision making : putting rules into context Authors: Slater, Benjamin James Andrew. Abstract: Episodic memory, an important cognitive process in humans, relies on both contextual and temporal information to recall sequences of events accurately. While nonhuman animals are capable of understanding rules based on context and have shown capability in learning temporal sequences, the ability to flexibly shift between these types of information has yet to be demonstrated. This thesis aimed to explore the cognitive mechanisms behind adapting memory sequences to changing contexts in three species. Following work in Lister hooded rats, the study was extended to New world (Common marmosets) and Old world monkeys (Rhesus macaques) to assess each species’ proficiency in learning context-guided sequences. In addition, a noninvasive technique called transcranial ultrasound stimulation (TUS) was employed with the macaques to investigate potential underlying neurobiological pathways. The task design, consistent across all three species, involved learning visual object sequences (e.g., A-B or C-D) where the correct choice was contingent on one of two background contexts (e.g., blue or yellow). Results showed that rats and marmosets were proficient in learning sequences that remained constrained to a singular context but faced challenges with sequences involving a mid-trial contextual shift. Conversely, the macaques quickly mastered both fixed and context-switching sequences, facilitating further investigation into potential neurobiological mechanisms using TUS. Prior research suggests a possible role for the prefrontal-hippocampal circuitry in context-dependent learning, prompting us to apply targeted modulation to the hippocampus and prefrontal cortex separately. Notably, TUS of the anterior hippocampus enhanced performance during the initial stages of learning. In contrast, TUS of the prefrontal cortex enhanced performance in the later phases, particularly in trials that required a context shift mid-trial. Overall, this research highlights the evolutionary foundation of flexible learning and offers insights into neural modulation in primate cognition, particularly in how the brain adapts dynamically to contextual shifts when guiding memory sequences Description: PhD Thesis Wed, 01 Jan 2025 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6750 2025-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/6739 Title: Unraveling the neurological basis of Tinnitus by studying its initial onset and subsequent chronification Authors: Umashankar, Abishek Abstract: Despite tinnitus being too common and present (prevalence: 13%, remission rate: 17.1%), it is still unclear as to why tinnitus is generated and why it persists, thus making it challenging to come up with definitive treatments. For better understanding of tinnitus mechanism, it is warranted to analyse, how the tinnitus transits from its initial onset or acute stages (duration of tinnitus less than 4 weeks) until its chronic stage (duration of tinnitus greater than 6 months). We were motivated to carry out a tinnitus study with an aim to unravel the neurobiological basis of tinnitus by studying its initial onset until its subsequent chronification. We hypothesized that the neural processes such as synchrony and gain (auditory hypersensitivity) linked to tinnitus will be maximal around the onset and reduces over time as a regression to the mean. The study involved individuals with Acute Tinnitus, who were monitored longitudinally for six months post-onset, alongside individuals with Chronic Tinnitus and a Control group matched to the Acute Tinnitus cohort. Our results culminating multiple measures (subjective and objective) of tinnitus reveal that the neural processes linked solely to the tinnitus activity were maximal around the time of onset and reduced over time which is in line with our hypothesis. We further established that measures of generalized auditory sensitivity (gain) do not significantly differ between the groups. Increased dynamic range adaptation, were observed in the Acute Tinnitus group, but not in the Chronic Tinnitus or Control groups thus indicating that tinnitus is an outcome of excess auditory hyperactivity as an invariance (mitigator) to central gain through properties of increased dynamic range adaptation that tends to persist through modes of sustained attentional networks. This would explain why tinnitus generates and persists as it seeks to modulate excessive hypersensitivity within the auditory system. Description: PhD Thesis Wed, 01 Jan 2025 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6739 2025-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/6736 Title: Living with a lower-grade glioma : exploring the potential for supported self-management Authors: Rimmer, Ben Abstract: Background: Lower-grade gliomas (LGG) are a subgroup of primary malignant brain tumours. People with LGG may live long-term with tumour-specific symptoms and impairments (e.g. seizures, cognitive impairment), alongside the uncertainty of an incurable condition. Supported self-management can improve clinical and psychosocial outcomes, such as quality-of-life (QoL). However, the self-management experiences of people with LGG are unclear. This thesis aimed to understand the lived experiences of people with LGG and the potential for supported self-management, from multiple perspectives. Methods: A quantitative systematic review of health-related QoL in people with LGG was followed by three semistructured interview sets. These comprised purposive samples of people with LGG (n=28), informal caregivers (IC) (e.g. partners) (n=19), and healthcare professionals (HCP) who support adults with brain tumours (n=25). Participants were recruited across the United Kingdom, through four National Health Service hospitals and the Brain Tumour Charity. Interviews were audio-recorded, transcribed, then analysed using inductive thematic analysis, framework method, or directed content analysis. Results: Findings are reported across six publications. People with LGG experience extensive QoL impacts (e.g. seizures, fatigue), with considerable implications on day-to-day life (e.g. work, relationships). They show willingness to self-manage but several factors (e.g. knowledge, health status) influence their ability to self-manage effectively. ICs provide wide-ranging support (e.g. practical, healthcare advocacy) but experience difficulties with preserving the care recipient’s independence. HCPs can empower people with LGG and ICs with the necessary tools and information, though challenges (e.g. identifying support needs, HCP collaboration) hinder the implementation of self-management support. Conclusions: This thesis provides novel and comprehensive understanding of the need, and potential for, supported self-management in people with LGG. These insights could extend to other brain tumours or progressive neurological conditions. Overall, this represents critical groundwork for the development and implementation of person-centred self-management support, to improve the QoL of this underserved population. Description: D. App. Ed. Psy. Thesis Wed, 01 Jan 2025 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6736 2025-01-01T00:00:00Z